Bortezomib-based intensification treatment improves PFS after induction therapy in multiple myeloma
Click Here to Manage Email Alerts
Response-adapted intensification treatment with a bortezomib-based regimen improved PFS among patients with newly diagnosed multiple myeloma who achieved minimal or partial response to immunomodulatory induction therapy, according to results of a randomized phase 3 study published in The Lancet Haematology.
The triplet intensification therapy also demonstrated a manageable safety profile; however, it did not improve OS.
“The etiology and progression of multiple myeloma are driven by the accumulation of acquired genetic events that affect clonal competition within the bone marrow microenvironment,” Graham H. Jackson, MD, professor at Northern Institute for Cancer Research at Newcastle University in England, and colleagues wrote. “Tumor cell diversity increases as genetic lesions accumulate, and the disease progresses from monoclonal gammopathy of undetermined significance to myeloma, leading to substantial subclonal heterogeneity at the time of diagnosis.”
Induction treatment intended to eliminate susceptible clones may provide selective pressure to expand resistant clones, leading to early or late relapse. Combination chemotherapies have been shown to improve clinical outcomes over single-agent chemotherapy by maximizing tumor cell death and eliminating resistant clones.
In the open-label, adaptive design Myeloma XI trial, researchers sought to determine if treatment intensification with cyclophosphamide, bortezomib (Velcade, Millennium/Takeda) and dexamethasone (CVD) could improve PFS and OS among patients with multiple myeloma who had suboptimal responses after immunomodulatory drug-based induction therapy.
The trial included three potential randomizations: induction treatment, intensification treatment and maintenance treatment. Jackson and colleagues reported the results of 583 adults (median age, 66 years; range, 57-72) with newly diagnosed multiple myeloma who had been randomly assigned to response-adapted intensification with CVD (n = 289; 61% men) or to no intensification treatment (n = 294; 54% men).
All patients had achieved partial or minimal response following induction therapy with cyclophosphamide, thalidomide and dexamethasone or cyclophosphamide, lenalidomide (Revlimid, Celgene) and dexamethasone.
Patients in the CVD group received up to eight, 21-day cycles of 500 mg oral cyclophosphamide on days 1, 8 and 15; 1.3 mg/m2 subcutaneous or IV bortezomib on days 1, 4, 8 and 11; and 20 mg oral dexamethasone on days 1, 2, 3, 5, 8, 9, 11 and 12.
PFS and OS from intensification randomization to data cutoff served as co-primary endpoints.
Median follow-up after randomization was 29.7 months (interquartile range [IQR], 17-43.5).
Results showed median PFS of 30 months (95% CI, 25-36) for the CVD group and 20 months (95% CI, 15-28) for the group that did not receive CVD (HR = 0.6; 95% CI, 0.48-0.75).
Neither group reached median OS. Researchers observed no difference in 3-year OS rates, which were 77.3% (95% CI, 71-83.5) for the CVD group and 78.5% (95% CI, 72.3-84.6) for the group that did not receive CVD (HR = 0.98; 95% CI, 0.67-1.43).
Grade 3 and grade 4 adverse events in the CVD group included neutropenia (n = 18), thrombocytopenia (n = 19) and anemia (n = 8). No patients died as a result of treatment in the CVD group.
“Taken together our data suggest that, in the case of suboptimal response to initial treatment, agent class should be switched rapidly with the aim of response intensification,” Jackson and colleagues wrote. “Although patients who do not respond to the induction therapy might still benefit from autologous haemopoietic stem cell transplantation, these data support the maximization of response before transplantation, given that the depth of response is associated with improved outcomes.”
The benefit of response-adapted intensification among certain patient subsets suggests clonal heterogeneity may be a key resistance mechanism in high-risk multiple myeloma that could be overcome by combinations of drugs with difference mechanisms of action, Francesca Patriarca, MD, of the hematology and transplant center unit at Udine University Hospital in Italy, wrote in an related editorial.
“Once a molecular risk stratification that surpasses conventional prognostication tools and reflects the entire biological heterogeneity of multiple myeloma is designed, we can envisage personalized treatment strategies at diagnosis, with more intense and complex induction regimens in high-risk patients and less toxic schemes in standard-risk patients,” Patriarca wrote. – by John DeRosier
Disclosures: Jackson reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Patriarca reports honoraria from Celgene, Janssen-Cilag and Takeda.
Read more about
Click Here to Manage Email Alerts